TY - JOUR
T1 - An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy
AU - Thiele, Nikki A.
AU - Brown, Victoria
AU - Kelly, James M.
AU - Amor-Coarasa, Alejandro
AU - Jermilova, Una
AU - MacMillan, Samantha N.
AU - Nikolopoulou, Anastasia
AU - Ponnala, Shashikanth
AU - Ramogida, Caterina F.
AU - Robertson, Andrew K.H.
AU - Rodríguez-Rodríguez, Cristina
AU - Schaffer, Paul
AU - Williams, Clarence
AU - Babich, John W.
AU - Radchenko, Valery
AU - Wilson, Justin J.
N1 - Funding Information:
This work was supported by Cornell University and by a Pilot Award from the Weill Cornell Medical College Clinical and Translational Science Center, funded by NIH/NCATS UL1TR00457. This research made use of the NMR Facility at Cornell University, which is supported in part by the NSF under award number CHE-1531632. TRIUMF receives funding via a contribution agreement with the National Research Council of Canada. We thank TRIUMF≫s ISAC facility for ion beam delivery and Drs. Peter Kunz and Jens Lassen for help with collecting 225Ac and 225Ra samples. We also thank Dr. Eszter Boros at Stony Brook University for providing us with trastuzumab, and Dr. J. David Warren of the Milstein Core Chemistry Facility at Weill Cornell Medicine for the use of equipment for analysis and purification.
Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2017/11/13
Y1 - 2017/11/13
N2 - The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.
AB - The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.
KW - actinium
KW - cancer
KW - chelates
KW - macrocycles
KW - radiopharmaceuticals
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U2 - 10.1002/anie.201709532
DO - 10.1002/anie.201709532
M3 - Article
C2 - 28963750
AN - SCOPUS:85031428200
SN - 1433-7851
VL - 56
SP - 14712
EP - 14717
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 46
ER -
